Gradual release medicine carrier

ABSTRACT

A medicament carried within a perforate or semipermeable shell is gradually released, as by dissolution into body fluids, to provide effective therapy with reduced concentration and dosage. The medicament may be in dry powdered form. For treatment of the eye, the carrier comprises a capsule less than 1 millimeter in diameter which is placed in the conjunctival sac or mounted in a contact lens. The capsule may be colored for easy location and removal, may be absorbable by the body, or may gradually swell to allow washout by the tears. For glaucoma treatment, less than 1 milligram of pilocarpine or phospholine in a single sustained release capsule may be an adequate daily dosage. In another embodiment a soft contact lens itself may serve as the medicine containing carrier. For burn, ulcer, or wound treatment, the carrier may be of planar configuration or incorporated in a film forming spray comprising many minute particles or capsules each containing a medicament. The resultant film will protect the tissue from exposure, will provide sustained release medication, and may be absorbable to eliminate the need for removal with concomitant damage to newly formed granulation tissue.

[ GRADUAL RELEASE MEDICINE CARRIER [76] Inventor: Samuel V. Abraham,16026 Royal Oaks Rd., Encino, Calif. 91316v [22] Filed: Feb. 7, 1972[2]] Appl. No.: 224,138

[52] US. Cl. 128/260, 424/19 [51] Int. Cl A61m 31/00 [58] Field ofSearch 128/260, 268, 261, 249,

[56] References Cited UNITED STATES PATENTS 2,898,911 8/1959 Taylor128/249 3,185,625 5/1965 Brown 424/19 3,416,530 12/1968 Ness 128/2603,485,244 12/1969 Rosen 128/260 X 3,618,604 9/1971 Ness 128/2603,625,214 12/1971 Higuchi 128/260 3,630,200 l2/l97l Higuchi 128/2603,641,237 2/1972 Gould et al. 128/260 OTHER PUBLICATIONS Waltman andKaufman, Use of Hydrophilic Contact Lenses to lncrease OcularPenetration of Topical Drugs, Investigative Opthalmology 9, No. 4, pp.250-255.

Dabezies, Contact Lenses and Their Solutions: Principles, Eye, Ear, Nose& Throat Monthly, Vol. 45, 3-1966, pp- 82-84 & 112. Sedlacek,Possibilities of Application of Eye Drugs with the Aid of Gel-ContactLenses, Czech. Oftalmologia, Vol. 21, 6-1965, pp. 509-512.

Gasset and Kaufman, Therapeutic Uses of Hydro- [451 July 30, 1974 1philic Contact Lenses, American Journal of Opthamology, Vol. 69, 2-1970,pp. 252-259.

Primary ExaminerRichard A. Gaudet Assistant Examiner-,1. C. McGowanAttorney, Agent, or Firm-Flam & Flam 57 ABSTRACT A medicament carriedwithin a perforate or semipermeable shell is gradually released, as bydissolution into body fluids, to provide effective therapy with reducedconcentration and dosage. The medicament may be in dry powdered form.For treatment of the eye, the carrier comprises a capsule less than 1millimeter in diameter which is placed in the conjunctival sac ormounted in a contact lens. The capsule may be colored for easy locationand removal, may be absorbable by the body, or may gradually swell toallow washout by the tears. For glaucoma treatment, less than 1milligram of pilocarpine or phospholine in a single sustained releasecapsule may be an adequate daily dosage. In another embodiment a softcontact lens itself may serve as the medicine containing carrter.

For burn, ulcer, or wound treatment, the carrier may be of planarconfiguration or incorporated in a film forming spray comprising manyminute particles or capsules each containing a medicament. The resultantfilm will protect the tissue from exposure, will provide sustainedrelease medication, and may be absorbable to eliminate the need forremoval with concomitant damage to newly formed granulation tissue.

5 Claims, 6 Drawing Figures 1 GRADUAL RELEASE MEDICINE CARRIERBACKGROUND OF THE INVENTION 1. Field of the Invention The presentinvention relates to gradual release medicine carriers and particularlyto a capsular medicament carrier useful for prolonged release therapy ofthe eye and adapted for placement in the conjunctival sac and to othercarriers for treatment of superficial body areas.

2. Description of the Prior Art It is well known that the effectivenessof some medicinal agents is increased when the agent is released slowlyinto the host. This is particularly true of the eye, where the constantwashing by tears tends to dilute and flush away a medicine dropped ontothe cornea. A substantial portion of the actual medicament is lost, andthe remaining therapeutic portion is present at the eye for a relativelyshort period of time.

Sustained release therapy, wherein a small amount of medicine isreleased over a prolonged period of time, significantly decreases boththe concentration of medicament required and the total daily dosage.Such therapy is of value to patients who are sensitive either to themedication itself or to the preservative, vehicle or stabilizer usedwith the agent. For eye treatment, sustained release therapy is usefulfor continuous control of intraocular pressure or other ocularconditions (infections, etc.).

The reduced dosage and concentration achievable with sustained releasetherapy is illustrated by the pilocarpine treatment of open-angleglaucoma. To simulate gradual release of the medication, patients wereadministered I drops of pilocarpine over a hour period. The results werecompared with the response of patients given the conventional dosage oftwo or three drops per day of 1% to 4% pilocarpine. Ona sustainedrelease basis, the minimum effective dosage was found to be between l0and 30 micrograms per hour, equivalent to a 24 hour dose of 240 to 720micrograms. This is significantly less than the total dose of from 1500micrograms per day for a patient receiving 1% pilocarpine three timesdaily to 6000 micrograms in a patient receiving 4% pilocarpine threetimes daily. The investigators reported that If a suitable method ofprolonged release pilocarpine therapy could be developed, most patientswith wide-angle glaucoma would require a total 24-hour dose between and25 times less than that they are currently using. (See SimulatedSustained Release Pilocarpine Therapy and Aqueous Humor Dynamics by S.Lerman and B. Reininger, OPHTHALMOLOGY DIGEST, Sept., 1971.)

In the past, some sustained release medicine carriers have beensuggested, but none is useful for eye therapy. Typical is thepolysiloxane (silicone rubber) implant shown in the US. Pat. No.3,279,996 to D.M. Long, Jr. et al. That device comprises a tube about Icentimeter in length, fabricated of certain silicone rubber material(typically dimethylpolysiloxane), and containing a drug which is solublein and capable of diffusing through the silicone rubber at a constantrate. The carrier containing a relatively large supply of themedicament, is im-v infectives, anesthetics, and hormones. Sustainedrelease drug application through polysiloxane implants also showsimproved effectiveness over conventional therapy. For example, invivoexperiments were performed with rats using the steroid hormonalpreparation megestrol acetate. These experiments show that sustainedrelease of the hormone through a polysiloxane implant is 6 to 25 timesmore effective than subcutaneous injections in producing comparablebiological effect. (See C. Chang and F. Kinel, Sustained ReleaseHormonal Preparations: Biologic Effectiveness of Megestrol Acetate inSTEROIDS, Vol. 12, No. 6, Dec., 1968.)

While effective therapeutically, silicone rubber implants areinapplicable for eye usage. An objective of the present invention is toprovide a gradual release medicine carrier of sufficiently small size asto be placed in the conjunctival sac, or incorporated in a contact lensworn by the patient. Techniques for carrier insertion and disposal ofthe emptied capsule are set forth. Other embodiments for burn, ulcer,wound and implant therapy are discussed.

SUMMARY OF THE INVENTION In accordance with the present invention, thereis provided a sustained release medicine carrier comprising a capsulehaving a perforate or semipermeable shell and containing'a medicamentwhich is gradually released through the shell. Alternatively, themedicament may be impregnated in the capsule. For eye therapy, thecapsule preferably is less than 1 millimeter in diameter, permittingdeposit of the capsule in the conjunctival sac. The medicament, whichmay be in a dry, powdered form, dissolves in the tears to effectuateprolonged release into the eye. The capsule may he inert or have a pHmatching that of the tears.

To facilitate insertion, one or more capsules may be prepackaged in adropette. Coloring facilitates location of the emptied capsule forremoval from the conjunctival sac. Alternatively, the capsule may beabsorbable, or may swell so as to bewashed from the eye by tears aftersome period of time.

In other embodiments, the sustained release medicine carrier may beinserted in a contact lens, or the corneoscleral lens itself mayfunction as the medicament container. For burn, ulcer andwoundtreatment, very small medicament containing capsules ormedicine-impregnated particles may be incorporated in a spray forming afilm over the body area being treated. The film may be absorbable andapplied in layers, with the rate of absorption controlling themedicament release rate. Preformed, absorbable, gradual releasemedicament containing structures such as thin pads or implants also areenvisioned. Alternatively, the medicaments may be incorporated inlinquets, pellets, microspansules, ointments, suppositories, or chewabletablets, each facilitating gradual release of the medicament.

BRIEF DESCRIPTION OF THE DRAWINGS eral figures. These drawings, unlessdescribed as dia-.

grammatic or unless otherwise indicated, are to scale.

FIGS. 1 and 2 are greatly enlarged perspective views,

partly broken away, of gradual-release medicine carri-' ers for eyetherapy and respectively using a perforate shell and a semipermeablemembrane.

FIG. 3 is a pictorial view showing insertion of a gradual releasemedicine carrier into the conjunctival sac of the eye.

FIG. 4 is a perspective view of a prolonged release medicine carriermounted in a contact lens.

FIG. 5 illustrates the manner in which a soft contact lens may be usedas a medicament carrier.

FIG. 6 is a perspective view of a pad-shaped gradual release medicinecarrier useful, e.g., for burn treatment.

DESCRIPTION OF THE PREFERRED EMBODIMENTS The following detaileddescription is of the best presently contemplated modes of carrying outthe invention. This description is not to be taken in a limiting sense,but is made merely for the purpose of illustrating the generalprinciples of the invention since the scope of the invention is bestdefined by the appended claims.

Structural and operational characteristics attributed to forms of theinvention first described shall also be attributed to forms laterdescribed, unless such characteristics are obviously inapplicable orunless specific exception is made.

A gradual release medicine carrier 10 useful for eye therapy is shown inFIG. 1. Referring thereto, the carrier or capsule 10 comprises a casingor shell 11 which may be, but is not necessarily spherical. Containedwithin the shell 11 is a medicament l2, typically in dry, powdered form.The shell 11 is perforated to allow body fluids such as tears to enterthe capsule interior 13. The medicament l2 dissolves in such fluid andflows out through the perforated shell 11 in solution.

The medicine release rate is established by the size, shape and numberof the shell 11 perforations. By way of example, a capsule 10 may havejust a few relatively large openings 14 of V- or Y-shape. Such shapeestablishes a substantial flow area, but prohibits foreign bodies suchas dust in tears from entering the capsule 10. Alternatively, the shell11 may be perforated by multiple tiny holes or micropores 15. In anotherembodiment the medicament may be impregnated in the capsule shell or thecapsule may be solid with the medicament impregnated throughout.

In the alternative embodiment of FIG. 2, the capsule includes a shell 21having the characteristics of a semipermeable membrane. Body fluiddiffuses through the membrane 21 into the capsule interior 23 where itcomes in contact with the dry, powdered medicament 12. The medicinedissolves, and the solution flows back out through the shell 21 at arate established by the membrane characteristics. Alternatively, aliquid medicament may be contained in the capsule 20, and thesemipermeable membrane selected for preferred outward diffusion of themedicine. The shell 21 may comprise a dialysis membrane.

Preferably the diameter of each capsule 10, 20 is sufficiently small sothat there is no irritation or discomfort when the carrier is situatedin the conjunctival sac of the eye. A diameter of less than about Imillimeter is satisfactory. The shell 11, 21 may be inert or may have apH of about 7.2, equal to that of a tear, and should be non-allergenic.

FIG. 3 illustrates delivery of the capsule 10,20 to the conjunctiva] sac25 of a patient 26. Many of the capsules 10, 20 may be packaged in abottle, in a saline or antiseptic solution. The capsules may be coloredfor ease of visability. An eyedropper is used to remove one or twocapsules from the bottle for deposit into the sac 25. Since the capsules10, 20 are small, it may be difficult to pick up only one or two in adropper. This problem is alieviated by prepackaging a very small number(i.e., one or two) capsules 10, 20 in an individual, disposable dropette27 or ampoule-like dropper. In use, the dropette 27 is opened and thecontents deposited into the conjunctival sac 25 as the lid 28 (FIG. 3)is held away from the eye 29.

While the capsule 10, 20 is within the conjunctiva! sac 25, themedicament 12 will dissolve in the patients tears and flow onto the eye29. Prolonged release of the medicine is achieved, so that the amount ofmedicament 12 employed may be very small. For example, in the treatmentof glaucoma the medicament 12 may comprise powdered crystals ofpilocarpine 0r phospholine. When gradually released from the carrier 10,20, less than 1 milligram of such powder may constitute a days supply.As discussed earlier, this is significantly less than the amountrequired for effective therapy using the conventional liquid dropapplication. Moreover, as the pilocarpine or phospholine is maintainedin dry powder form, no preservative is required, eliminating the chanceof allergic reaction to such preservatives. Similarly, no preservativemay be required if the medicament is impregnated in the capsule.

When all of the medicament 12 has been released to the eye 29, thecapsule 10, 20 is removed from the sac 25 by flushing the eye withwater, or by use of a cue tip. If the shell 11, 21 is colored, thecapsule readily can be located for removal.

The need to remove the emptied capsule 10, 20 from the sac 25 can beeliminated by making the shell 11, 21 of a material absorbed by thebody. For example, the perforated shell 11 may be made of a syntheticpolyglycolic acid polymer which hydrolyzes in the human body. Suturesmade of such synthetic material are sold commercially by the LederleLaboratories, Pearl River, N.Y., under the trademark DEXON. Certaincolloidal materials such as collagen fibrils may be formed into a shell11 absorbably in the body. Alternatively, the semipermeable shell 21 maycomprise absorbable gut of the type used for dialysis membranes. Suchmaterial is absorbed in the body by proteolysis, a protein cleavageprocess.

An alternative approach to the capsule removal problem is to form theshell 11, 21 of a material which will swell'when immersed in tears. Inthe course of a day, as the medicament 12 is dispensed, the shell willswell sufiiciently so as to be washed from the eye by the tears presentin the sac 25. A swelling gelatin material satisfactory for use at theeye is described in the Mar., 1968 issue of ARCH OPHTHAL, on page 289.This gelatin is absorbed by the body, but only after periods much longerthan a day.

Rather than placing the gradual release medicine carrier in theconjunctival sac, the capsule 10, 20 may be situated in a contact lens.Thus (FIG. 4) a contact lens 35 may include a capsule receiving notch orrecess 36 in a peripheral edge 37 of the lens. A capsule 10, 20 isinjected into the recess 36. When the lens 35 is placed on the eye,tears will enter the recess 36; the medicament 12 will dissolve in thetears and flow onto the eye 29 as before.

The use of the invention with soft contact lenses is of particularinterest. The hydrophilic corneoscleral lens, composed of a cross-linkedhydrophilic polymer of 2- hydroxyethyl methacrylic acid has the knowndisadvantage that bacteria tend to grow in the interstices of theplastic. As a result, such lenses normally must be boiled in saline eachday for sterilization, or kept in a sterilizing solution overnight withquestionable results. Such daily sterilization could be eliminated bymounting in the lens a capsule 10, 20 containing an antibacterial agentinstead of or in addition to a medicament.

Another disadvantage of soft contact lenses is that ocular preservativessuch as benzalkonium chloride and chlorbutanol drops might concentratewithin the interstices of the lens. This problem is completelyeliminated by the use of a carrier 10, 20 which contains the medicamentwithout any preservative.

As the cost of soft contact lenses is reduced, it is likely thatdisposable lenses will become available. The medicament carrier 10, 20could be mounted in such a disposable lens at the time of manufacture.The user would purchase the daily disposable lenses by prescriptionspecifying the appropriate medication.

In yet another embodiment, a disposable, soft contact lens itself mayserve as the medicament shell. Thus in FIG. 5, the soft contact lens 40contains a chamber 41 containing the medicament l2, injected duringmanufacture. The region 41 is perforated, as for example, by micropores42 analogous to the openings in the embodiment of FIG. 1. Controlledrelease of the medicine is achieved directly from the lens 40.

For the treatment of burns, ulcers and wounds, the carrier 45 (FIG. 6)may comprise a pad of minimal thickness but relatively large length andwidth. The casing 46 of the pad 45 is analogous in composition andfunction to the shell 11 or 12 described above, and surrounds a hollowinterior 47 containing a medicament 48. Preferably the casing 46 is ofabsorbable material. When placed on a burn or open wound, the medicament48 slowly will be released. Eventually the casing 46 itself will beabsorbed. The slow release of medication provides the benefits oflowered dosage and concentration, while the absorbability featureeliminates the pain usually associated with bandage removal. The padneed not be hollow, but may have the medicament impregcine releasecharacteristics described above. In addition, the film will protect thetissue from exposure, decreasing pain and reducing the chance of toxicreactions. The medicament may include an antiseptic to preventinfection.

Additional benefits result from using an absorbable film formingmaterial. The rate of medicament release may be determined by theabsorption rate. Additional layers may be sprayed on to affect thedosage and replenish the medication. Further,use of such an absorbablefilm eliminates the problem, associated with removal of conventionalwound coverings, of pulling off newly formed granulation tissue.

Suitably packaged forms of the invention, for example linguets orsuppositories, can be placed in the mucus membrane of the eye, oral ornasal cavity, vagina or rectum to achieve gradual release of medicament.

Intending to claim all novel, useful and unobvious features is shown ordisclosed, the applicant claims:

1. For sustained release medicinal therapy of the eye:

a sealed, disposable, ampoule-like dropper prepackaged to contain a verysmall number of gradual release medicine carriers in a saline orantiseptic solution, each carrier having a hollow casing containing amedicament in dry powdered form, said casing being non-allergenic,having a tear-equivalent pH, and being perforated by orifices to allowthe entry of tear fluids, the number and size of said orificesestablishing the gradual release rate of said medicament by dissolutioninto said tear fluids, each carrier having no dimension greater thanabout 1 millimeter to permit non-irritating disposition of said carrierin the conjunctival sac of the eye, said ampoule-like dropperfacilitating delivery of said carriers into said conjunctival sac forintimate tear fluid exchanging delivery of said medicament to the eye.

2. A prepackaged ampoule-like dropper according to claim 1 wherein saidcasing is absorbable by tissue of said conjunctival sac over a timeduration commensurate with or greater than the total release period ofsaid medicament.

3. A prepackaged ampoule-like dropper according to claim 1 wherein saidcarrier is colored to aid finding the emptied casing for removal fromsaid conjunctival sac.

4. A prepackaged ampoule-like dropper according to claim 1 wherein saidcasing gradually swells in the presence of tears to a size sufficient tobe washed from said conjunctival sac by said tears.

5. A prepackaged ampoule-like dropper according to claim 1 wherein saidmedicament comprises less than I milligram of pilocarpine orphospholine, said medicament being a sufficient daily dosage for thesustained release treatment of glaucoma.

2. A prepackaged ampoule-like dropper according to claim 1 wherein saidcasing is absorbable by tissue of said conjunctival sac over a timeduration commensurate with or greater than the total release period ofsaid medicament.
 3. A prepackaged ampoule-like dropper according toclaim 1 wherein said carrier is colored to aid finding the emptiedcasing for removal from said conjunctival sac.
 4. A prepackagedampoule-like dropper according to claim 1 wherein said casing graduallyswells in the presence of tears to a size sufficient to be washed fromsaid conjunctival sac by said tears.
 5. A prepackaged ampoule-likedropper according to claim 1 wherein said medicament comprises less than1 milligram of pilocarpine or phospholine, said medicament being asufficient daily dosage for the sustained release treatment of glaucoma.